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British Journal of Pharmacology Nov 2021P-glycoprotein (P-gp) exhibits a broad substrate specificity and affects pharmacokinetics, especially intestinal absorption. However, prediction, in vivo, of...
BACKGROUND AND PURPOSE
P-glycoprotein (P-gp) exhibits a broad substrate specificity and affects pharmacokinetics, especially intestinal absorption. However, prediction, in vivo, of P-gp-mediated drug-drug interaction (DDI) and non-linear absorption at the preclinical stage, is challenging. Here we evaluate the use of human MDR1 mouse artificial chromosome (hMDR1-MAC) mice carrying human P-gp and lacking their own murine P-gp to quantitatively predict human P-gp-mediated DDI and non-linear absorption.
EXPERIMENTAL APPROACH
The P-gp substrates (aliskiren, betrixaban, celiprolol, digoxin, fexofenadine and talinolol) were administered orally to wild-type, Mdr1a/b-knockout (KO) and hMDR1-MAC mice, and their plasma concentrations were measured. We calculated the ratio of area under the curve (AUCR) in mice (AUC /AUC or AUC /AUC ) estimated as attributable to complete P-gp inhibition and the human AUCR with and without P-gp inhibitor administration. The correlations of AUCR with AUCR and AUCR were investigated. For aliskiren, betrixaban and celiprolol, the K and V values for P-gp in hMDR1-MAC mice and humans were optimized from different dosing studies using GastroPlus. The correlations of K and V for P-gp between human and hMDR1-MAC mice were investigated.
KEY RESULTS
A better correlation between AUCR and AUCR (R = 0.88) was observed. Moreover, good relationships of K (R = 1.00) and V (R = 0.98) for P-gp between humans and hMDR1-MAC mice were observed.
CONCLUSIONS AND IMPLICATIONS
These results suggest that P-gp-mediated DDI and non-linear absorption can be predicted using hMDR1-MAC mice. These mice are a useful in vivo tool for quantitatively predicting P-gp-mediated disposition in drug discovery and development.
Topics: ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Drug Interactions; Intestinal Absorption; Mice; Pharmaceutical Preparations
PubMed: 34232502
DOI: 10.1111/bph.15612 -
Current Pharmaceutical Design 2016P-glycoprotein is an ATP-binding cassette transporter involved in drug absorption, distribution and excretion. It pumps a wide range of xenobiotic compounds out of the... (Review)
Review
P-glycoprotein is an ATP-binding cassette transporter involved in drug absorption, distribution and excretion. It pumps a wide range of xenobiotic compounds out of the cells and plays a crucial role in Multi Drug Resistance. Moreover, recent studies have demonstrated that changes in P-gp function and/or expression at the blood brain barrier are implicated in the pathogenesis of neurological disorders such as therapy-refractory epilepsy, Alzheimer's and Parkinson's disease. In the last decades the studies have been addressed to the discovery of potent P-gp inhibitors able to revert pharmacoresistance and to the development of PET tracers to detect P-gp activity and expression for an early diagnosis and therapy monitoring of neurodegenerative disease. However, clinical trials have reported only limited success in reversing MDR and radiolabeled ligands were not actually useful to study differences of transporter function in different brain regions due to their low brain uptake. The difficulties into the discovery of new ligands is due to the use of different experimental assays, to the fact that P-gp is highly flexible protein with different binging sites and available crystallographic structures for the protein have inadequate resolution. To overcome these limitations research groups prefer computational approaches such as homology models in their structure-based design or ligand-based methodologies. A recent approach aimed to identify ligands which can interrupt ATP-binding and hydrolysis by P-gp, by interacting at the NBDs of the protein. In this review results from radiolabeled, substrates and inhibitors, for monitoring the activity and expression of P-gp, respectively, are presented.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Drug Design; Humans; Ligands
PubMed: 27514711
DOI: 10.2174/1381612822666160810114008 -
Nanomedicine : Nanotechnology, Biology,... Feb 2022Multidrug resistance (MDR) in cancer chemotherapy is a growing concern for medical practitioners. P-glycoprotein (P-gp) overexpression is one of the major reasons for... (Review)
Review
Multidrug resistance (MDR) in cancer chemotherapy is a growing concern for medical practitioners. P-glycoprotein (P-gp) overexpression is one of the major reasons for multidrug resistance in cancer chemotherapy. The P-gp overexpression in cancer cells depends on several factors like adenosine triphosphate (ATP) hydrolysis, hypoxia-inducible factor 1 alpha (HIF-1α), and drug physicochemical properties such as lipophilicity, molecular weight, and molecular size. Further multiple exposures of anticancer drugs to the P-gp efflux protein cause acquired P-gp overexpression. Unique structural and functional characteristics of nanotechnology-based drug delivery systems provide opportunities to circumvent P-gp mediated MDR. The primary mechanism behind the nanocarrier systems in P-gp inhibition includes: bypassing or inhibiting the P-gp efflux pump to combat MDR. In this review, we discuss the role of P-gp in MDR and highlight the recent progress in different nanocarriers to overcome P-gp mediated MDR in terms of their limitations and potentials.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Antineoplastic Agents; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Neoplasms
PubMed: 34775061
DOI: 10.1016/j.nano.2021.102494 -
Expert Opinion on Drug Metabolism &... May 2021: Expression of P-glycoprotein (P-gp) increases toward the distal small intestine, implying that the duodenum is the preferential absorption site for P-gp substrate... (Review)
Review
: Expression of P-glycoprotein (P-gp) increases toward the distal small intestine, implying that the duodenum is the preferential absorption site for P-gp substrate drugs. Oral bioavailability of poorly soluble P-gp substrate drugs is low and varied but increases with high-fat meals that supply lipoidal components and bile in the duodenum.: Absorption properties of P-gp substrate drugs along with factors and oral dosage formulations affecting their solubility and bioavailability were reviewed with PubMed literature searches. An overview is provided from the viewpoint of the 'spring-and-parachute approach' that generates supersaturation of poorly soluble P-gp substrate drugs.: The oral bioavailability of P-gp substrate drugs is difficult to predict because of their low solubility, preferential absorption sites, and overlapping substrate specificities with CYP3A4, along with the scattered intestinal P-gp expression/function. To attain high and steady oral bioavailability of poorly soluble P-gp substrate drugs, physicochemical modification of drugs to improve solubility, or oral dosage formulations that generate long-lasting supersaturation in the duodenum, is preferred. In particular, supersaturable lipid-based drug delivery systems that can increase passive diffusion and/or lymphatic absorption are effective and applicable to many poorly soluble P-gp substrate drugs.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Administration, Oral; Animals; Biological Availability; Chemistry, Pharmaceutical; Drug Delivery Systems; Humans; Intestinal Absorption; Lipids; Pharmaceutical Preparations; Solubility
PubMed: 33703995
DOI: 10.1080/17425255.2021.1902986 -
Epilepsy & Behavior : E&B Aug 2021Sudden unexpected death in epilepsy (SUDEP) is the major cause of death that affects patients with epilepsy. The risk of SUDEP increases according to the frequency and... (Review)
Review
Sudden unexpected death in epilepsy (SUDEP) is the major cause of death that affects patients with epilepsy. The risk of SUDEP increases according to the frequency and severity of uncontrolled seizures; therefore, SUDEP risk is higher in patients with refractory epilepsy (RE), in whom most antiepileptic drugs (AEDs) are ineffective for both seizure control and SUDEP prevention. Consequently, RE and SUDEP share a multidrug resistance (MDR) phenotype, which is mainly associated with brain overexpression of ABC-transporters such as P-glycoprotein (P-gp). The activity of P-gp can also contribute to membrane depolarization and affect the normal function of neurons and cardiomyocytes. Other molecular regulators of membrane potential are the inwardly rectifying potassium channels (Kir), whose genetic variants have been related to both epilepsy and heart dysfunctions. Although it has been suggested that dysfunctions of the cardiac, respiratory, and brainstem arousal systems are the causes of SUDEP, the molecular basis for explaining its dysfunctions remain unknown. In rats, repetitive seizures or status epilepticus induced high expression of P-gp and loss Kir expression in the brain and heart, and promoted membrane depolarization, malignant bradycardia, and the high rate of mortality. Here we reviewed clinical and experimental evidences suggesting that abnormal expression of depolarizing/repolarizing factors as P-gp and Kir could favor persistent depolarization of membranes without any rapid functional recovery capacity. This condition induced by convulsive stress could be the molecular mechanism leading to acquired severe bradycardia, as an ineffective heart response generating the appropriate scenario for SUDEP development. This article is part of the Special Issue "NEWroscience 2018".
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Death, Sudden; Epilepsy; Humans; Potassium; Rats; Risk Factors; Sudden Unexpected Death in Epilepsy
PubMed: 31706919
DOI: 10.1016/j.yebeh.2019.106590 -
Molecular Oncology Jan 2023Chemotherapy resistance is a persistent clinical problem in relapsed high-risk neuroblastomas. We tested a panel of 15 drugs for sensitization of neuroblastoma cells to...
Chemotherapy resistance is a persistent clinical problem in relapsed high-risk neuroblastomas. We tested a panel of 15 drugs for sensitization of neuroblastoma cells to the conventional chemotherapeutic vincristine, identifying tariquidar, an inhibitor of the transmembrane pump P-glycoprotein (P-gp/ABCB1), and the ERBB family inhibitor afatinib as the top resistance breakers. Both compounds were efficient in sensitizing neuroblastoma cells to vincristine in trypan blue exclusion assays and in inducing apoptotic cell death. The evaluation of ERBB signaling revealed no functional inhibition, that is, dephosphorylation of the downstream pathways upon afatinib treatment but direct off-target interference with P-gp function. Depletion of ABCB1, but not ERRB4, sensitized cells to vincristine treatment. P-gp inhibition substantially broke vincristine resistance in vitro and in vivo (zebrafish embryo xenograft). The analysis of gene expression datasets of more than 50 different neuroblastoma cell lines (primary and relapsed) and more than 160 neuroblastoma patient samples from the pediatric precision medicine platform INFORM (Individualized Therapy For Relapsed Malignancies in Childhood) confirmed a pivotal role of P-gp specifically in neuroblastoma resistance at relapse, while the ERBB family appears to play a minor part.
Topics: Animals; Humans; ATP Binding Cassette Transporter, Subfamily B, Member 1; Vincristine; Afatinib; Zebrafish; Drug Resistance, Neoplasm; Neuroblastoma; ATP Binding Cassette Transporter, Subfamily B; ErbB Receptors; Recurrence; Cell Line, Tumor
PubMed: 36181342
DOI: 10.1002/1878-0261.13318 -
AAPS PharmSciTech Jan 2022Significant research efforts have been devoted to unraveling the mystery of P-glycoprotein(P-gp) in drug delivery applications. The efflux membrane transporter P-gp is... (Review)
Review
Significant research efforts have been devoted to unraveling the mystery of P-glycoprotein(P-gp) in drug delivery applications. The efflux membrane transporter P-gp is widely distributed in the body and accountable for restricting drug absorption and bioavailability. For these reasons, it is the primary cause of developing multidrug resistance (MDR) in most drug delivery applications. Therefore, P-gp inhibitors must be explored to address MDR and the low bioavailability of therapeutic substrates. Several experimental models in kinetics and dynamic studies identified the sensitivity of drug molecules and excipients as a P-gp inhibitor. In this review, we aimed to emphasize nonionic surface-active agents for effective reversal of P-gp inhibition. As it is inert, non-toxic, noncharged, and quickly reaching the cytosolic lipid membrane (the point of contact with P-gp efflux protein) enables it to be more efficient as P-gp inhibitors. Moreover, nonionic surfactant improves drug absorption and bioavailability through the various mechanism, involving (i) association of drug with surfactant improves solubilization, facilitating its cell penetration and absorption; (ii) weakening the lateral membrane packing density, facilitating the passive drug influx; and (iii) inhibition of the ATP binding cassette of transporter P-glycoprotein. The application of nonionic surfactant as P-gp inhibitors is well established and supported by various experiments. Altogether, herein, we have primarily focused on various nonionic surfactants and their development strategies to conquer the MDR-causing effects of P-gp efflux protein in drug delivery. Graphical Abstract.
Topics: ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Drug Resistance, Multiple; Pharmaceutical Preparations; Surface-Active Agents
PubMed: 35043278
DOI: 10.1208/s12249-022-02211-1 -
Drug Development Research Jun 2022P-glycoprotein (P-gp) is a transporter protein that is come under the ATP binding cassette family of proteins. It is situated on the surface of the intestine epithelium,... (Review)
Review
P-glycoprotein (P-gp) is a transporter protein that is come under the ATP binding cassette family of proteins. It is situated on the surface of the intestine epithelium, where P-gp substrate binds to the transporter and is pumped into the intestine lumen by the ATP-driven energy-dependent process. In this review, we summarize the role of the P-gp efflux transporter situated on the intestine, the clinical importance of P-gp related drug interactions, and approaches to minimize the effect of P-gp in drug transport. This review also focuses on the impact of P-gp on the bioavailability of the orally administered drug. Many drug's oral bioavailabilities can improve by concomitant use of P-gp inhibitors. Multidrug resistance are reduced by using some naturally occurring compounds obtained from plants and several synthetic P-gp inhibitors. Formulation strategies, one of the most important approaches to mimic the P-gp transporter's action, finally enhancing the oral bioavailability of the drug by inhibiting its P-gp efflux. Vitamin E TPGS, Gelucire 44/14 and other pharmaceutical/formulation excipients inhibit the P-gp efflux. A prodrug approach might be a useful strategy to overcome drug resistance. Prodrug helps to enhance the solubility or alter the pharmacokinetic properties but does not diminish the pharmacological action.
Topics: ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Adenosine Triphosphate; Biological Availability; Prodrugs
PubMed: 35103340
DOI: 10.1002/ddr.21918 -
Journal of Controlled Release :... Jul 2021P-Glycoprotein serves as a gatekeeper in the blood-brain-barrier wherein, it shows a vital part in the elimination of xenobiotics, drugs, foreign molecules etc. and... (Review)
Review
P-Glycoprotein serves as a gatekeeper in the blood-brain-barrier wherein, it shows a vital part in the elimination of xenobiotics, drugs, foreign molecules etc. and guards the central nervous system from infections and external toxic molecules by functioning as an efflux transporter. It plays an essential role in various brain-related conditions like Parkinsonism, Alzheimer's disease, depression, cancer, etc. and terminates the entry of therapeutic agents across blood-brain-barrier which remains a significant challenge serving as major hindrance in pharmacotherapy of disease. The physiological structure and topology of P-glycoprotein and its relation with blood-brain-barrier and central nervous system gives an idea for targeting nanocarriers across the barrier into brain. This review article provides an overview of current understanding of the nanoformulations-based P-gp trafficking strategies like nanocarriers, stem cell therapy, drugs, substrates, polymeric materials, chemical compounds as well as naturally occurring active constituents for improving drug transport in brain across blood-brain-barrier and contributing in effective nanotherapeutic development for treatment of CNS disorders.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Alzheimer Disease; Biological Transport; Blood-Brain Barrier; Brain; Humans
PubMed: 34087246
DOI: 10.1016/j.jconrel.2021.05.046 -
Expert Opinion on Drug Delivery Aug 2015The most commonly used immunosuppressive drugs (ISDs) which can prevent rejection of transplanted organs include cyclosporine, tacrolimus, mycophenolate mofetil,... (Review)
Review
INTRODUCTION
The most commonly used immunosuppressive drugs (ISDs) which can prevent rejection of transplanted organs include cyclosporine, tacrolimus, mycophenolate mofetil, sirolimus and everolimus. The clinical efficacy of these drugs is greatly influenced by their in vivo performance. Various pharmacokinetic and toxicological constraints limit their therapeutic activity which is a matter of serious concern.
AREAS COVERED
An extensive review establishes that poor solubility in intestinal milieu; substantial gut metabolism by CYP3A along with simultaneous efflux by P-glycoprotein and significant hepatic first-pass metabolism are all potential hindrances resulting in poor oral absorption of highly lipophilic ISDs. On top of that, toxicities accompanied by ISDs further affect their overall therapeutic efficacy.
EXPERT OPINION
This review discusses various barriers to the efficient absorption of ISDs and the potential formulation strategies for resolving such ambiguities. The article highlights the potential role of lymphatic targeting by means of novel lipid nanocarriers in modifying systemic availability, toxicity and efficacy profiles of ISDs. Finally, the present manuscript discusses that integration of P-glycoprotein and CYP inhibitors in lipid nanocarrier system provides a novel perspective of overcoming the significant barriers that leads to poor bioavailability of ISDs.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Biological Availability; Drug Delivery Systems; Humans; Immunosuppressive Agents
PubMed: 25642742
DOI: 10.1517/17425247.2015.1005072